Proton therapy for cancer treatment has gained much recognition and attracted great interest in recent years as evidenced by the increasing number of proton radiation therapy facilities in the United States and around the world. The reason for this interest is that proton therapy could further improve the results of cancer treatments by applying very conformal dose distributions with less dose delivered to healthy tissues than with even the most advanced photon therapy techniques. Another reason is the promise from industry to develop more compact and less expensive proton technology. One unsolved problem in proton therapy is the current inability to predict the exact range of protons in tissue due to inaccuracy of converting CT Hounsfield units to proton stopping power and the lack of a low-dose imaging modality in the treatment room predicting the range of protons on a day-to-day basis. This is unfortunate, because the major promise of protons is the ability to stop the radiation in front of a critical normal tissue structure positioned behind a tumor. The technological limitation mostly responsible for this uncertainty is the use of x-ray based computed tomography (xCT) for proton treatment planning and the lack of a low-dose modality for daily treatment-room image guidance. The reason for using xCT is its wide availability and established role in radiation therapy treatment planning and image guidance. Here, we are proposing to overcome the current limitations of xCT by using proton computed tomography (pCT) for proton treatment planning and image guidance in the treatment room. With this effort at the interface of physics and medicine, we will leverage our experience of recent years in developing a prototype pCT scanner and advanced image reconstruction methods. We will make the transition from the current prototype scanner to a clinical pCT scanner. The prototype will be used to demonstrate the value of pCT in comparison to x-ray CT (specific aim 1). We will also study the technological limitations of the prototype and, with the help of our collaborators in high energy physics and computer science and engineering, develop a head pCT scanner that is suitable for clinical applications (specific aim 2). Lastly, we will develop engineering concepts with a commercial proton therapy partner and prepare the stage for a controlled technology transfer (specific aim 3). The deliverable of this proposal will be a clinical pCT head scanner for thorough evaluation of the value of pCT for clinical applications in proton therapy and as a low-dose CT imaging modality. If successful, this research and development will shift the current paradigm that proton treatment planning can only be based on x-ray CT, toward the use of more accurate pCT-based planning and pCT-image guided proton therapy. This will open the door for entirely new clinical proton treatment protocols to be tested in clinical trials.